Premium
Ras inhibits endoplasmic reticulum stress in human cancer cells with amplified Myc
Author(s) -
YaariStark Shira,
Shaked Maayan,
NevoCaspi Yael,
JacobHircsh Jasmine,
Shamir Ron,
Rechavi Gideon,
Kloog Yoel
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25102
Subject(s) - unfolded protein response , endoplasmic reticulum , small hairpin rna , biology , cancer research , cell culture , programmed cell death , microbiology and biotechnology , small interfering rna , cell growth , neuroblastoma , k562 cells , mapk/erk pathway , apoptosis , transfection , gene knockdown , signal transduction , genetics
In neuroblastoma LAN‐1 cells harboring an amplified MycN gene, disruption of cooperation between Ras and MycN proteins by the Ras inhibitor farnesylthiosalicylic acid (FTS, Salirasib) reportedly arrests cell growth. Our aim was to establish whether this is a general phenomenon. We examined the effects of FTS on gene‐expression profiles, growth and death of NCIH929 myeloma cells and K562 leukemia cells, which—like LAN‐1 cells—exhibit Myc gene amplification and harbor active Ras. Under specified conditions, FTS reduced Ras and Myc and induced cell growth arrest and death in all Myc ‐amplified cell lines but not in SHEP, a neuroblastoma cell line without Myc gene amplification. Gene‐expression analysis revealed a common pattern of FTS‐induced endoplasmic reticulum (ER) stress, known as the unfolded protein response (UPR), in Myc ‐amplified cells, but not in SHEP. Thus, Ras negatively regulates ER stress in cells with amplified Myc . ER stress was also inducible by dominant‐negative (DN)‐Ras or shRNA to Ras isoforms, all of which induced an increase in BIP (the master regulator of ER stress) and its downstream targets Nrf2 and eIF2α, both regulated by active p‐PERK. FTS also induced an increase in p‐PERK, while small interfering RNA to PERK reduced Nrf2 and ATF4 and rescued cells from FTS‐induced death. BIP and its downstream targets were also increased by inhibitors of MAPK p38 and MEK. Ras, acting through MAPK p38 and MEK, negatively regulates the ER stress cascades BIP/PERK/Nrf2 and eIF2α/ATF4/ATF3. These findings can explain the Ras‐dependent protection of Myc ‐amplified cells from ER stress‐associated death.